Method for producing optically active 3-aminopiperidine or salt thereof

ABSTRACT

The present invention relates to a method for producing an optically active 3-aminopiperidine or salt thereof. In the method, a racemic nipecotamide is stereoselectively hydrolyzed to obtain an optically active nipecotamide and an optically active nipecotic acid in the presence of an enzyme source derived from an organism, and then the optically active nipecotamide is derived into an optically active aminopiperidine or salt thereof by aroylation, Hofmann rearrangement, deprotection of the amino group and further deprotection; or the optically active nipecotamide is derived into an optically active aminopiperidine or salt thereof by selective protection with BOC, Hofmann rearrangement and further deprotection. It is possible by the present invention to produce an optically active 3-aminopiperidine or salt thereof useful as a pharmaceutical intermediate from an inexpensive and easily available starting material by easy method applicable to industrial manufacturing.

TECHNICAL FIELD

The present invention relates to a method for producing an opticallyactive 3-aminopiperidine or salt thereof useful as a pharmaceuticalintermediate, and to intermediates useful for producing the3-aminopiperidine.

BACKGROUND ART

As methods for producing an optically active 3-aminopiperidine or saltthereof, or a derivative of optically active 3-aminopiperidine, forexample, the following methods are known:

1) a method, wherein L-ornithine monohydrochloride is methyl-esterified,and then (S)-3-amino piperidone is obtained by chromatography with anion exchange resin, the (S)-3-amino piperidone is reacted with lithiumaluminum hydride to be (S)-3-aminopiperidine, an inorganic salt isremoved by filtration, and the target compound is purified (Non-patentDocument 1);

2) a method, wherein ethyl nipecotate is optically resolved usingL-tartaric acid, the nitrogen atom is protected with benzyloxycarbonylgroup, the ethyl ester is hydrolyzed in alkaline condition, Curtiusrearrangement is carried out using diphenylphosphoryl azide, theresulting isocyanate is reacted with tert-butanol to obtain(R)-1-(benzyloxycarbonyl)-3-(tert-butoxy carbonylamino)piperidine, andfinally the benzyloxycarbonyl group is removed to produce(R)-3-(tert-butoxycarbonylamino) piperidine (Patent Document 1);

3) a method, wherein ethyl nipecotate is optically resolved usingL-tartaric acid and the nitrogen atom is protected withbenzyloxycarbonyl group as similar to the method 2), and then the ethylester is converted into an amide using ammonia, and subsequently Hofmannrearrangement is carried out to produce (R)-1-benzyl-3-aminopiperidine(Patent Document 2);

4) a method, wherein an (R)-1-(tert-butoxycarbonyl)nipecotic anhydridewith other acid is reacted with sodium azide to produce a carboxylicazide derivative, then Curtius rearrangement is carried out to obtain(R)-1-tert-butoxycarbonyl-3-(benzyloxy carbonylamino)piperidine, anddeprotection is carried out at the 3-position to produce(R)-1-(tert-butoxycarbonyl)-3-amino piperidine (Patent Document 3);

5) a method, wherein a racemic 1-benzyl-3-aminopiperidine is opticallyresolved using dibenzoyl-D-tartaric acid to produce(S)-1-benzyl-3-aminopiperidine (Patent Document 4);

6) a method, wherein the amino group of L-aspartic acid is protected,the carboxy group is reduced, the resulting hydroxyl group is convertedinto a leaving group, the leaving group is replaced by potassiumphthalimide and lithium cyanide, the phthalimide is hydrolyzed to obtain(S)-3-(N,N-dibenzylamino) piperidone, and finally the piperidone isreduced with lithium aluminum hydride to produce(S)-3-(N,N-dibenzylamino)piperidine (Non-patent Document 2);

7) a method, wherein the amino group of L-aspartic acid is protected,the carboxy group is reduced, the resulting hydroxyl group is convertedinto a leaving group, the resultant is reacted with ammonia to produce(S)-3-(tert-butoxycarbonyloxyamino) piperidine, the piperidine isreacted with benzylamine instead of ammonia to obtain(S)-1-benzyl-3-(tert-butoxycarbonyloxyamino) piperidine, anddeprotection is carried out using trifluoroacetic acid to produce(S)-1-benzyl-3-aminopiperidine (Non-patent Document 3).

However, the method of conventional art 1) is problematic andimpractical, since chromatography that is disadvantageous in industrialproduction and lithium aluminum hydride that is expensive and highlydangerous have to be used.

By the methods of conventional arts 2) to 7), a protected opticallyactive 3-aminopiperidine can be produced, and an optically active3-aminopiperidine can be produced by deprotecting the protected3-aminopiperidine. However, the methods have the following problems.

The methods of conventional arts 2) and 4) have a serious problem forindustrial implementation, since a reaction that utilizes an azidecompound exhibiting an explosion risk, i.e. Curtius rearrangement, hasto be carried out.

The productivity by the method of conventional art 3) is low, sinceyields of benzylation and Hofmann rearrangement process are low.

The starting material of the method of conventional art 5) is not easilyavailable, and a multistep synthetic reaction is needed to obtain thestarting material. In addition, expensive dibenzoyl-D-tartaric acid hasto be used as an optical resolving agent.

The method of conventional art 6) art has problems both in safety andeconomical efficiency, since the number of the steps is large, and ahighly toxic cyanide compound and an expensive reducing agent have to beused.

The method of conventional art 7) is also not advantageous in industrialproduction, since the number of the steps is large.

As mentioned above, all the presently known methods for producing anoptically active 3-aminopiperidine or salt thereof or derivative thereofhave problems in economical efficiency and safety or productivity; andthus, the methods are not practical for industrial implementation.

-   Patent Document 1: WO03/004496-   Patent Document 2: JP7-133273A-   Patent Document 3: WO01/068604-   Patent Document 4: JP7-330732A-   Non-patent Document 1: J. Chem. Soc. DALTON TRANS, 1987, 1127-1132-   Non-patent Document 2: J. Org. Chem., 2000, 65, 7406-7416-   Non-patent Document 3: Synthetic Communications, 1998, 28, 3919-3926

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

Under the above mentioned situation, the objective of the presentinvention is to provide a practical method for industrial productionthat can simply and easily produce an optically active 3-aminopiperidineor salt thereof useful as a pharmaceutical intermediate from aninexpensive readily available raw material, and intermediates useful forproducing the optically active 3-aminopiperidine or salt thereof.

Means for Solving the Problems

The present inventors have intensely studied in consideration of theabove; as a result, the inventors developed a method for simply andeasily producing an optically active 3-aminopiperidine or salt thereofuseful as a pharmaceutical intermediate from an inexpensive and readilyavailable raw material.

The present invention relate to a method for producing an opticallyactive nipecotamide derivative or an optically active nipecotinderivative, comprising steps of:

stereoselectively hydrolyzing a racemic nipecotamide derivativerepresented by the following formula (1):

wherein, R¹ represents a hydrogen atom or a benzyl group, by using anenzyme source having ability to stereoselectively hydrolyze the racemicnipecotamide derivative (1), to convert the racemic nipecotamidederivative (1) into a mixture of an optically active nipecotamidederivative represented by the following formula (2):

wherein, * indicates an asymmetric carbon atom; and R¹ means the same asthe above,and an optically active nipecotin derivative represented by thefollowing formula (3):

wherein, * and R¹ mean the same as the above;

and then isolating the optically active nipecotamide derivative (2) orthe optically active nipecotin derivative (3) from the mixture.

Further, the present invention relates to a method for producing anoptically active 1-aroyl-3-(protected amino)piperidine derivative,comprising steps of:

aroylating optically active nipecotamide represented by the followingformula (2′):

wherein, * indicates an asymmetric carbon atom,to produce an optically active 1-aroylnipecotamide derivativerepresented by the following formula (4):

wherein, * indicates an asymmetric carbon atom; Ar represents anoptionally substituted aryl group having 6 to 15 carbon atoms;

and then producing an optically active 1-aroyl-3-aminopiperidinederivative represented by the following formula (5):

wherein, * and Ar mean the same as the above,by Hofmann rearrangement at the amide group;

and further aroylating or carbamating the amino group forcrystallization or extraction to isolate the optically active1-aroyl-3-(protected amino)piperidine derivative represented by thefollowing formula (6):

wherein, * and Ar mean the same as the above; R² represents anoptionally substituted aroyl group having 7 to 15 carbon atoms, analkyloxycarbonyl group having 2 to 15 carbon atoms, analkenyloxycarbonyl group having 3 to 15 carbon atoms, an aryloxycarbonylgroup having 7 to 15 carbon atoms, or an aralkyloxycarbonyl group having8 to 15 carbon atoms.

Furthermore, the present invention relates to an optically active1-aroylnipecotamide derivative represented by the following formula (4):

wherein, * indicates an asymmetric carbon atom; Ar represents a phenylgroup, a p-methylphenyl group or a p-chlorophenyl group.

The present invention also relates to an optically active1-aroyl-3-aminopiperidine derivative represented by the followingformula (5):

wherein, * indicates an asymmetric carbon atom; Ar represents a phenylgroup, a p-methylphenyl group or a p-chlorophenyl group.

Further, the present invention relates to an optically active1-aroyl-3-(protected amino)piperidine derivative represented by thefollowing formula (6):

wherein, * indicates an asymmetric carbon atom; Ar represents a phenylgroup, a p-methylphenyl group or a p-chlorophenyl group; R² represents abenzoyl group, a p-methylbenzoyl group, a p-chlorobenzoyl group or atert-butoxycarbonyl group.

Effect of the Invention

According to the method of the present invention, it is possible tosimply and easily produce an optically active 3-aminopiperidine or saltthereof useful as a pharmaceutical intermediate, and intermediatesuseful for producing the 3-aminopiperidine, from an inexpensive andreadily available raw material.

BEST MODE FOR CARRYING OUT THE INVENTION

The outline of the present invention can be shown by the followingscheme.

The present invention is described below for every step in order.

Step 1

In the present step, a racemic nipecotamide derivative represented bythe following formula (1):

wherein, R¹ represents a hydrogen atom or a benzyl group, isstereoselectively hydrolyzed by using an enzyme source having an abilityto stereoselectively hydrolyze the racemic nipecotamide derivative (1),to convert the racemic nipecotamide derivative (1) into a mixture of anoptically active nipecotamide derivative represented by the followingformula (2):

wherein, * indicates an asymmetric carbon atom; and R¹ means the same asthe above,and an optically active nipecotin derivative represented by thefollowing formula (3):

wherein, * and R¹ mean the same as the above;and then the optically active nipecotamide derivative (2) or theoptically active nipecotin derivative (3) is isolated from the mixture.

In the present invention, the “enzyme source” includes not only anenzyme having the above hydrolysis activity, but also a culture of amicroorganism having the hydrolysis activity and processed productthereof. The “culture of a microorganism” means a bacterialcell-containing culture solution or a cultured bacterial cell; and the“processed product thereof” means, for example, a crude extract, afreeze-dried microbiality, an acetone-dried microbiality, a groundproduct of the bacterial cell, or the like, and includes such productsso long as the products have the hydrolysis activity. In addition, theenzyme source can be immobilized by well-known means and be used as animmobilized enzyme or an immobilized mycelium. The immobilization can becarried out by a method known to those skilled in the art, such ascrosslinking, physical adsorption and entrapment.

The each microorganism described below in the specification is availablefrom International Patent Organism Depositary and other researchinstitutions. For example, microorganisms specified by the NBRC numberare available from National BioResource Project Chrysanthemum;microorganisms specified by the FERM number are available fromInternational Patent Organism Depositary, National Institute of AdvancedIndustrial Science and Technology; microorganisms specified by the IAMnumber are available from The University of Tokyo Center forBioinformatics; and microorganisms specified by the JCM number areavailable from RIKEN BioResource Center-Japan Collection ofMicroorganisms.

In the present step, the enzyme source having the ability tostereoselectively hydrolyze the racemic nipecotamide derivative (1) isnot limited; however, is derived from, for example, a microorganismbelonging to genus Achromobacter, Brevibacterium, Cupriavidus,Pectobacterium, Pseudomonas, Rhodococcus or Staphylococcus.

As the enzyme source having the ability to stereoselectively hydrolyzethe S-enantiomer of the nipecotamide derivative, the enzyme sourcederived from the microorganism belonging to genus Achromobacter,Cupriavidus, Pseudomonas and Rhodococcus are exemplified.

As such an enzyme source, the enzyme sources derived from amicroorganism selected from the group consisting of Achromobacterxylosoxidans subsp. xylosoxidans, Cupriavidus sp., Pseudomonaschlororaphis and Rhodococcus erythropolis are preferably exemplified;and the microorganism is more preferably Achromobacter xylosoxidanssubsp. Xylosoxidans NBRC13495, Cupriavidus sp. KNK-J915 (FERM BP-10739),Pseudomonas chlororaphis NBRC3904 or Rhodococcus erythropolis IAM1440.

As the enzyme source having the ability to stereoselectively hydrolyzethe R-enantiomer of the racemic nipecotamide derivative, the enzymesource derived from the microorganism belonging to genus Brevibacterium,Pseudomonas, Pectobacterium or Staphylococcus is exemplified.

As such an enzyme source, the enzyme source derived from a microorganismselected from the group consisting of Brevibacterium iodinum,Pseudomonas fragi, Pectobacterium carotovorum subsp. carotovorum andStaphylococcus epidermidis are preferably exemplified; and themicroorganism is more preferably Brevibacterium iodinum NBRC3558,Pseudomonas fragi NBRC3458, Pectobacterium carotovorum subsp.Carotovorum NBRC12380 or Staphylococcus epidermidis JCM2414.

Either a wild-type strain or a variant strain may be used as themicroorganism having the productivity of the hydrolase. Alternatively, amicroorganism induced by genetic techniques such as cell fusion or genemanipulation can also be used. The microorganism that produces such agene-engineered enzyme can be obtained by method, for example, includinga step of isolating and/or purifying an enzyme to determine a part of orall the amino acid sequences of the enzyme, a step of obtaining the DNAsequence encoding the enzyme on the basis of the amino acid sequence, astep of introducing the DNA into another microorganism to obtain arecombinant microorganism, and a step of cultivating the recombinantmicroorganism to obtain the enzyme, as described in WO98/35025; or thelike. The recombinant microorganism as described above includes amicroorganism transformed by the plasmid having DNA that encodes thehydrolase. In addition, Escherichia coli is preferred as a hostmicroorganism.

The culture medium for the microorganism used as the enzyme source isnot particularly limited as long as the microorganism can grow. Forexample, a usual liquid media can be used that contain glucides such asglucose and sucrose, alcohols such as ethanol and glycerol, fatty acidssuch as oleic acid and stearic acid and esters thereof, and oils such asrapeseed oil and soybean oil, and the like, as carbon sources; ammoniumsulfate, sodium nitrate, peptone, casamino acid, corn steep liquor,bran, yeast extract, and the like, as nitrogen sources; magnesiumsulfate, sodium chloride, calcium carbonate, potassium monohydrogenphosphate, potassium dihydrogen phosphate, and the like, as inorganicsalts; malt extract, meat extract, and the like, as other nutrientsources. In addition, an inducer may be added to the medium for inducingthe enzyme production of microorganism.

The inducer includes nitrile, lactam compound, amide, and the like. Theexample of the nitrile includes acetonitrile, isovaleronitrile,propionitrile, pivalonitrile, n-butyronitrile, isobutyronitrile,n-capronitrile, 3-pentenenitrile, and the like; the example of thelactam compound includes γ-butyrolactam, δ-valerolactam, ε-caprolactam,and the like; and the example of the amide includes crotonamide,benzamide, propionamide, acetamide, n-butyl amide, isobutylamide,n-valeric amide, n-capronamide, methacrylamide, phenylacetamide,cyclohexanecarboxamide, and the like. The additive amount of the inducerto the medium is from 0.05% to 2.0%, preferably from 0.1% to 1.0%.

The cultivation can be aerobically carried out, and typically theincubation time is about from 1 to 5 days, the pH of the medium is from3 to 9, the incubation temperature is from 10 to 50° C.

In the present invention, the stereoselective hydrolysis reaction of theracemic nipecotamide derivative (1) can be carried out by adding theracemic nipecotamide derivative (1) as a substrate and a culture of themicroorganism or processed product thereof or the like into a suitablesolvent, and stirring the mixture while the pH is adjusted. Although thereaction conditions vary depending on the enzyme, the microorganism orprocessed product thereof to be used, the substrate concentration, andthe like, typically the substrate concentration can be about from 0.1 to100% by weight, preferably from 1 to 60% by weight, the reactiontemperature can be from 10 to 60° C., preferably from 20 to 50° C., thepH of the reaction can be from 4 to 11, preferably from 6 to 9, and thereaction time can be from 1 to 120 hours, preferably from 1 to 72 hours.The substrate can be collectively or continuously added. The reactioncan be carried out batchwise or continuously.

The optically active nipecotamide derivative and optically activenipecotic acid derivative generated by the reaction can be each isolatedand purified by the common procedure. For example, the reaction mixtureincluding the optically active nipecotamide derivative generated by thehydrolysis reaction is treated with sodium hydroxide or the like, andextracted with an organic solvent such as ethyl acetate or toluene, andthe organic solvent is evaporated under reduced pressure, and the targetcompound can be isolated and purified by distillation,recrystallization, chromatography or the like. Additionally, thefiltrate prepared by removing the cell of the microorganism from thereaction mixture is neutralized and crystallized using sodium hydroxideor the like, and then the precipitated target compound is filtrated forisolation and purification.

The method of producing optically active 3-aminopiperidine or saltthereof from optically active nipecotamide via step 2 to step 5 isdescribed below.

Step 2

In the present step, an optically active 1-aroylnipecotamide derivativerepresented by the following formula (4):

wherein, * indicates an asymmetric carbon atom; Ar represents anoptionally substituted aryl group having 6 to 15 carbon atoms, isproduced by aroylating optically active nipecotamide represented by thefollowing formula (2′):

wherein, * indicates an asymmetric carbon atom.

In the present invention, an aryl group preferably includes a phenylgroup, a naphthyl group and a biphenyl group, preferably a phenyl group.The substituent includes an alkyl group having 1 to 12 carbon atoms, analkenyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to12 carbon atoms, an aryl group having 6 to 12 carbon atoms, a fluorineatom, a chlorine atom, a bromine atom, an iodine atom, an alkyloxy grouphaving 1 to 12 carbon atoms, an alkylthio group having 1 to 12 carbonatoms, a nitro group, an amino group, a nitroso group, a hydroxyl group,a sulfonic acid group, a sulfonamide group, a carboxylic acid group, aformyl group, an acyl group having 2 to 12 carbon atoms, an aroyl grouphaving 7 to 12 carbon atoms, a cyano group, an alkyloxycarbonyl grouphaving 2 to 12 carbon atoms, a trifluoromethyl group, and the like. Thesubstituent is preferably an alkyl group having 1 to 12 carbon atoms anda chlorine atom.

Ar is particularly preferably a phenyl group, a p-methylphenyl group anda p-chlorophenyl group, and the optically active 1-aroyl nipecotamidederivative (4) in which the Ar is the groups is a novel compound unknownin literatures.

The method for producing the optically active nipecotamide representedby the formula (2′) that is a starting material of the present step isnot particularly limited; and, for example, the optically activenipecotamide in which R¹ in the formula (2) produced in step 1 is ahydrogen atom may be used, and the compound produced according to themethod described in JP7-133273 A and like may be used.

In the present step, the nitrogen atom of the compound (2′) is aroylatedby reacting an aroylating agent in the presence of a base.

The aroylating agent includes acid anhydrides such as benzoic anhydride,p-methylbenzoic anhydride and p-chlorobenzoic anhydride, and acidchlorides such as benzoyl chloride, p-toluoyl chloride andp-chlorobenzoyl chloride.

The use amount of the aroylating agent is preferably 0.5 to 10 times bymole, more preferably 1 to 5 times by mole, relative to the compound(2′).

The base is not particularly limited, and the example thereof includestertiary amines such as triethylamine, tri-n-butylamine, N-methylmorpholine, N-methylpiperidine, diisopropylethylamine, pyridine,N,N-dimethylaminopyridine and 1,4-diazabicyclo[2,2,2]octane; metalhydroxides such as lithium hydroxide, sodium hydroxide, potassiumhydroxide, barium hydroxide and magnesium hydroxide; metal carbonatessuch as lithium carbonate, sodium carbonate and potassium carbonate;metal bicarbonate salts such as lithium hydrogen carbonate, sodiumhydrogen carbonate and potassium hydrogen carbonate; and metal alkoxidessuch as lithium methoxide, lithium ethoxide, sodium methoxide, sodiumethoxide, potassium methoxide, potassium ethoxide andpotassium-tert-butoxide.

The base is preferably lithium hydroxide, sodium hydroxide, potassiumhydroxide, lithium carbonate, sodium carbonate and potassium carbonate,more preferably sodium hydroxide and potassium hydroxide.

The use amount of the base is preferably 0.1 to 10 times by mole, morepreferably 1 to 5 times by mole, relative to the compound (2′).

The reaction solvent of the present step includes water; alcoholicsolvents such as methanol, ethanol and isopropanol; ether type solventssuch as tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether;ester solvents such as ethyl acetate and isopropyl acetate; hydrocarbonsolvents such as benzene, toluene, xylene and hexane; ketone solventssuch as acetone and methyl ethyl ketone; nitrile solvents such asacetonitrile, propionitrile and benzonitrile; halogen type solvents suchas methylene chloride, chloroform and chlorobenzene; amide solvents suchas N,N-dimethylformamide and N,N-dimethylacetoamide; sulfoxide solventssuch as dimethyl sulfoxide; urea solvents such as dimethylpropyleneurea; and triamide phosphonate solvents such as triamidehexamethylphosphonate. One of the solvents may be singly used, or two ormore solvents may be used in combination. Water is preferred.

The use amount of the solvent is preferably 50 times or less by weight,more preferably 20 times or less by weight, relative to the compound(2′).

When the present reaction is carried out in a water-containing solvent,hydrolysis of the aroylating agent proceeds. Thus, in such a case, it ispreferable that the reaction may be carried out while the pH of thereaction mixture is adjusted, and the aroylating agent and the base aregradually added. The pH of the reaction mixture is preferably from 6 to14, more preferably from 7 to 11.

The reaction temperature of the present step is preferably from −20 to80° C., more preferably from 0 to 50° C. Although the reaction time ofthe step is not particularly limited, the time is preferably from 30minutes to 24 hours, more preferably from 1 to 6 hours.

Though the addition method and addition order of the compound (2′), thebase, the aroylating agent and the reaction solvent upon the reactionare not particularly limited, as described previously, the base and thearoylating agent are preferably gradually added to a mixture of thecompound (2′) and the reaction solvent while the pH is adjusted.

The reaction mixture obtained in the present step may also be useddirectly in the subsequent step, and if necessary, may also bepost-processed. General treatment for obtaining a product from areaction mixture may be carried out as post-processing. For example,water or, as necessary, an aqueous acid solution such as an hydrochloricacid or diluted sulfuric acid is added to the reaction mixture aftercompletion of the reaction for neutralization; and extraction may becarried out using a general extraction solvent such as ethyl acetate,diethyl ether, methylene chloride, toluene, hexane. The reaction solventand extraction solvent are evaporated from the thus obtained extract byan operation such as heating under reduced pressure to obtain the targetcompound.

Although the thus obtained target compound has a purity enough to beusable in the following step, the purity may also be further improved bya general purification measure such as crystallization, fractionaldistillation or column chromatography for the purpose of furtherimproving the yield in the following step or the purity of a compoundobtained in the following step.

Alternatively, when the compound (4) that is a product is alreadyprecipitated in the reaction mixture as crystal, the crystal may besimply separated. As the method of separating the crystal, pressurefiltration, vacuum filtration and centrifugal separation may also be allacceptable. The crystal may also be washed with water or an organicsolvent in order to further improve the purity of the crystal.

The organic solvent includes alcoholic solvents such as methanol,ethanol and isopropanol; ether type solvents such as tetrahydrofuran,1,4-dioxane and ethylene glycol dimethyl ether; ester solvents such asethyl acetate and isopropyl acetate; hydrocarbon solvents such asbenzene, toluene, xylene and hexane; ketone solvents such as acetone andmethyl ethyl ketone; nitrile solvents such as acetonitrile,propionitrile and benzonitrile; halogen type solvents such as methylenechloride, chloroform and chlorobenzene. One of the solvents may besingly used, or two or more solvents may be used in combination. Theorganic solvent is preferably ethyl acetate, toluene, xylene, hexane andchlorobenzene.

Step 3

In the present step, an optically active 1-aroyl-3-aminopiperidinederivative represented by the following formula (5):

wherein, * and Ar mean the same as the above,is produced by Hofmann rearrangement at the amide group of the opticallyactive 1-aroylnipecotamide derivative which is produced in Step 2 andrepresented by the following formula (4):

wherein, * and Ar mean the same as the above.

Particularly, the optically active 1-aroyl-3-aminopiperidine derivative(5) in which Ar is a phenyl group, a p-methylphenyl group or ap-chlorophenyl group is a novel compound unknown in literatures.

The Hofmann rearrangement can be carried out by reacting the compound(4) with an oxidizing agent and a base.

The oxidizing agent includes, for example, chlorine, bromine and sodiumhypochlorite, preferably sodium hypochlorite. When sodium hypochloriteis used, aqueous solution thereof may be used from the viewpoints ofstorage stability and easiness of handling. The concentration of theaqueous solution is preferably from 5 to 30% by weight.

The use amount of the oxidizing agent is preferably 1 to 10 times bymole, more preferably 1 to 3 times by mole, relative to the compound(4).

The base includes, for example, metal hydroxides such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide andmagnesium hydroxide; metal alkoxides such as lithium methoxide, lithiumethoxide, sodium methoxide, sodium ethoxide, potassium methoxide,potassium ethoxide and potassium tert-butoxide. The base is preferablylithium hydroxide, sodium hydroxide and potassium hydroxide.

The use amount of the base is preferably 0.5 to 30 times by mole, morepreferably 3 to 15 times by mole, relative to the compound (4).

The reaction temperature of the present step is preferably from −20 to100° C., more preferably from −5 to 70° C. The reaction time of the stepis preferably from 30 minutes to 24 hours, more preferably from 1 to 12hours.

The reaction solvent of the step is not particularly limited, and waterand a general organic solvent can be used. Among them, water ispreferred. The usable organic solvent includes alcoholic solvents suchas methanol, ethanol and isopropanol; ether type solvents such astetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether; estersolvents such as ethyl acetate and isopropyl acetate; hydrocarbonsolvents such as benzene, toluene and hexane; ketone solvents such asacetone and methyl ethyl ketone; nitrile solvents such as acetonitrileand propionitrile; halogen type solvents such as methylene chloride andchloroform; amide solvents such as N,N-dimethylformamide andN,N-dimethylacetoamide; sulfoxide solvents such as dimethyl sulfoxide;urea solvents such as dimethylpropylene urea; and triamide phosphonatesolvents such as triamide hexamethylphosphonate. One of the solvents maybe singly used, or two or more solvents may be used in combination. Whentwo or more solvents are used, the mixing ratio is not particularlylimited.

The use amount of the solvent is preferably 50 times or less by weight,more preferably 20 times or less by weight, relative to the compound(4).

The addition method and addition order of the compound (4), theoxidizing agent, the base and the reaction solvent upon the reaction arenot particularly limited, and the oxidizing agent may be added dropwiselastly from the viewpoint of improving the yield.

As for the processing after the reaction, extraction using ethylacetate, toluene and isopropyl ether, which are representativeextraction solvents, is difficult, since the compound (5) obtained inthe present step typically exhibits high water solubility. On the otherhand, the compound (5) can be extracted if a large amount of an organicsolvent having a large polarity, such as tetrahydrofuran or isopropanol,is used. However, in such a case, inorganic salt and organic impurityare also extracted together, whereby it is difficult to obtain thecompound (5) with high purity. The present inventors intensely studiedthe problem; as a result, found that the compound is converted into awater-insoluble compound by carrying out step 4 described below, and itbecomes easy to isolate the compound.

Step 4

In the present step, the amino group of the optically active1-aroyl-3-aminopiperidine derivative which is produced in Step 3 andrepresented by the following formula (5):

wherein, * and Ar mean the same as the above,is aroylated or carbamated to produce an optically active1-aroyl-3-(protected amino)piperidine derivative represented by thefollowing formula (6):

wherein, * and Ar mean the same as the above; R² represents anoptionally substituted aroyl group having 7 to 15 carbon atoms, analkyloxycarbonyl group having 2 to 15 carbon atoms, analkenyloxycarbonyl group having 3 to 15 carbon atoms, an aryloxycarbonylgroup having 7 to 15 carbon atoms, or an aralkyloxycarbonyl group having8 to 15 carbon atoms. Then, the compound (6) having improved purity isisolated with crystallization using water or extraction with an organicsolvent.

R² is preferably a benzoyl group, an o-methylbenzoyl group, am-methylbenzoyl group, a p-methylbenzoyl group, an o-chlorobenzoylgroup, a m-chlorobenzoyl group, a p-chlorobenzoyl group, ap-methoxybenzoyl, a p-nitrobenzoyl group, a 3,4-dichlorobenzoyl group, atert-butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonylgroup, an n-propoxycarbonyl group, an isopropoxycarbonyl group, ann-butoxycarbonyl group, an isobutoxycarbonyl group, an allyloxycarbonylgroup and phenyloxycarbonyl group, more preferably a benzoyl group, ap-methylbenzoyl group, a p-chlorobenzoyl group and a tert-butoxycarbonylgroup. The optically active 1-aroyl-3-(protected amino)piperidinederivative (6) in which R² represents the above groups is a novelcompound unknown in literatures.

The aroylation or carbamation of the present step is carried out byreacting an aroylating agent or a carbamating agent in the presence of abase.

The aroylating agent includes acid anhydrides such as benzoic anhydride,p-methylbenzoic anhydride and p-chlorobenzoic anhydride, and acidchlorides such as benzoyl chloride, p-methylbenzoyl chloride andp-chlorobenzoyl chloride. The agent is preferably acid chlorides such asbenzoyl chloride, p-methylbenzoyl chloride and p-chlorobenzoyl chloride.

The carbamating agent includes di-tert-butyl dicarbonate, dibenzyldicarbonate, methyl chlorocarbonate, ethyl chlorocarbonate, n-propylchlorocarbonate, isopropyl chlorocarbonate, n-butyl chlorocarbonate,isobutyl chlorocarbonate, allyl chlorocarbonate, phenyl chlorocarbonateand benzyl chlorocarbonate, preferably di-tert-butyl dicarbonate andbenzyl chlorocarbonate.

The use amount of the aroylating agent or carbamating agent ispreferably 0.5 to 10 times by mole, more preferably 1 to 5 times bymole, relative to the compound (5).

The base is not particularly limited, and the example thereof includestertiary amines such as triethylamine, tri-n-butylamine, N-methylmorpholine, N-methylpiperidine, diisopropylethylamine, pyridine,N,N-dimethylaminopyridine and 1,4-diazabicyclo[2,2,2]octane; metalhydroxides such as lithium hydroxide, sodium hydroxide, potassiumhydroxide, barium hydroxide and magnesium hydroxide; metal carbonatessuch as lithium carbonate, sodium carbonate and potassium carbonate;metal bicarbonate salts such as lithium hydrogen carbonate, sodiumhydrogen carbonate and potassium hydrogen carbonate; and metal alkoxidessuch as lithium methoxide, lithium ethoxide, sodium methoxide, sodiumethoxide, potassium methoxide, potassium ethoxide andpotassium-tert-butoxide. The base is preferably lithium hydroxide,sodium hydroxide, potassium hydroxide, lithium carbonate, sodiumcarbonate and potassium carbonate, more preferably sodium hydroxide andpotassium hydroxide.

The use amount of the base is preferably 0.1 to 10 times by mole, morepreferably 1 to 5 times by mole, relative to the amount of the compound(5).

The reaction solvent of the present step is a solvent used in step 3,and is preferably water. An organic solvent may be further added, asrequired, for the purpose of improving at least one of the promotion ofthe reaction, yield improvement, improvement of liquid properties, andthe like.

The hydrolysis of the aroylating agent or carbamating agent proceedswhen water is contained in the reaction solvent of the step. Thus, insuch a case, the reaction may be carried out while the pH of thereaction mixture is adjusted and the aroylating agent or carbamatingagent and the base are gradually added.

The pH of the reaction mixture is preferably from 6 to 14, morepreferably from 7 to 11.

The reaction temperature of the present step is preferably from −20 to80° C., more preferably from 0 to 50° C.

Although the reaction time of the step is not particularly limited, thetime is preferably from 30 minutes to 24 hours, more preferably from 1to 6 hours.

Though the method and order of addition of the compound (5), the base,the aroylating agent or carbamating agent and the reaction solvent uponthe reaction are not particularly limited, as described previously, thebase and the aroylating agent or carbamating agent are preferablygradually added to the mixture of the compound (5) and the reactionsolvent while the pH is adjusted.

When the compound (6) that is the product is already precipitated ascrystal in the reaction mixture, the crystal may directly be separatedas the treatment after the reaction. As the method for separating thecrystal, pressure filtration, vacuum filtration and centrifugalseparation may also be all acceptable. The crystal may also be washedwith water or an organic solvent in order to further improve the purityof the crystal.

The organic solvent includes alcoholic solvents such as methanol,ethanol and isopropanol; ether type solvents such as tetrahydrofuran,1,4-dioxane and ethylene glycol dimethyl ether; ester solvents such asethyl acetate and isopropyl acetate; hydrocarbon solvents such asbenzene, toluene, xylene and hexane; ketone solvents such as acetone andmethyl ethyl ketone; nitrile solvents such as acetonitrile,propionitrile and benzonitrile; halogen type solvents such as methylenechloride, chloroform and chlorobenzene. One of the solvents may besingly used, or two or more solvents may be used in combination. Theorganic solvent is preferably ethyl acetate, toluene, xylene, hexane andchlorobenzene.

Alternatively, the compound (6) that is the product may also beextracted with an organic solvent for isolation as another method.

The organic solvent is not particularly limited so long as the solventis difficult to be mixed with water, and preferably includes ether typesolvents such as tetrahydrofuran, 1,4-dioxane and ethylene glycoldimethyl ether; ester solvents such as ethyl acetate and isopropylacetate; hydrocarbon solvents such as benzene, toluene, xylene andhexane; halogen type solvents such as methylene chloride, chloroform andchlorobenzene; more preferably ethyl acetate, toluene, xylene,chlorobenzene, and the like.

The use amount of the organic solvent is preferably 50 times or less byweight, more preferably 20 times or less by weight, relative to thecompound (6).

It is preferable to carry out extraction at room temperature or higher,preferably at 50 to 130° C., in order to improve the solubility of thecompound (6) in the organic solvent to thereby reduce the use amount ofthe solvent.

The product through steps 1 to 4 contains an optically active1-aroylnipecotic acid as impurity, represented by the following formula(11):

wherein, * and Ar mean the same as the above.In order to remove the compound, the pH of the water layer may bepreferably adjusted to be 7 or higher, more preferably from 9 to 14.

The purity of the compound (6) separated with extraction can be improvedby evaporating the solvent by the operation such as heating underreduced pressure. When the compound (6) has good crystallinity, thecompound may be crystallized and purified to obtain the compound (6)with high quality. The impurity to be removed includes the compound(11), the enantiomer of the compound (6), the excessive aroylating agentor carbamating agent, and the like. The method for crystallizing thecompound (6) may be any crystallization methods such as crystallizationby cooling an extract, crystallization by concentrating under reducedpressure and crystallization by adding a poor solvent such as hexane andheptane.

Step 5

In the present step, optically active 3-aminopiperidine or salt thereofrepresented by the following formula (7):

wherein, * indicates an asymmetric carbon atom,is produced by hydrolyzing the optically active 1-aroyl-3-(protectedamino)piperidine derivative which is produced in Step 4 and isrepresented by the following formula (6):

wherein, *, Ar and R² mean the same as the above.

In the present step, compound (6) is reacted with an acid or a base forhydrolysis. Preferably, an acid may be used.

The base is not particularly limited, and the example thereof includessodium hydroxide, potassium hydroxide and lithium hydroxide.

The use amount of the base is preferably 20 times or less by mole, morepreferably 1 to 10 times by mole, relative to the amount of the compound(6).

The acid is not particularly limited, and the example thereof includesmineral acids such as hydrogen chloride, hydrogen bromide, sulfuric acidand nitric acid; and sulfonic acids such as trifluoromethane sulfonicacid, p-toluenesulfonic acid and methanesulfonic acid. The acid ispreferably hydrogen chloride, hydrobromic acid and sulfuric acid, morepreferably hydrogen chloride. Although the acid may be used directly,the aqueous solution thereof is preferably used.

The use amount of the acid is preferably 50 times or less by mole, morepreferably 1 to 20 times by mole, relative to the compound (6).

The reaction temperature of the present step is preferably from 30° C.to 200° C., more preferably from 50° C. to 140° C.

Although the reaction time of the step is not particularly limited, thetime is preferably from 1 to 40 hours, more preferably from 5 to 30hours.

The reaction solvent of the step is water, and an organic solvent may befurther added for the purpose of the promotion of the reaction, theimprovement of the liquid properties, and the like.

The organic solvent includes alcoholic solvents such as methanol,ethanol and isopropanol; and ether type solvents such astetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether. One ofthe solvents may be singly used, or two or more solvents may be used incombination. When two or more solvents are used in combination, themixing ratio is not particularly limited.

The addition method and addition order of the compound (6), the acid andthe reaction solvent upon the reaction are not particularly limited.

General treatment for obtaining a product from a reaction mixture may becarried out as the treatment after the reaction. For example, asnecessary, an aqueous alkaline solution such as an aqueous sodiumhydroxide solution or aqueous potassium carbonate solution is added tothe reaction mixture after completion of the reaction forneutralization, and extraction may be carried out using a generalextraction solvent such as ethyl acetate, diethyl ether, methylenechloride, toluene, hexane or the like. The reaction solvent andextraction solvent are evaporated from the resulting extract by anoperation such as heating under reduced pressure to obtain the targetcompound.

Although the thus obtained target compound has purity enough to beusable in the following step, the purity may also be further improved bya general purifying method such as crystallization, fractionaldistillation or column chromatography for the purpose of furtherimproving the yield in the following step or the purity of a compoundobtained in the following step.

Alternatively, the reaction solvent may be evaporated from the reactionmixture by an operation such as heating under reduced pressure toisolate the target compound as a salt of the compound (7) and the acid,and crystallization may be carried out for the purpose of furtherimproving the purity.

The solvent for carrying out crystallization preferably includesalcoholic solvents such as methanol, ethanol and isopropanol; ether typesolvents such as tetrahydrofuran, 1,4-dioxane and ethylene glycoldimethyl ether; ester solvents such as ethyl acetate and isopropylacetate; hydrocarbon solvents such as benzene, toluene, xylene andhexane; and halogen type solvents such as methylene chloride, chloroformand chlorobenzene. One of the solvents may be singly used, or two ormore solvents may be used in combination. The solvent is more preferablymethanol, ethanol, ethyl acetate, toluene, xylene, chlorobenzene and thelike.

Moreover, optically active 3-aminopiperidine or salt thereof can beobtained also by the following scheme. Each step is described below inorder.

Step 6

In the present step, only optically active nipecotamide which isproduced in Step 1 and is represented by the following formula (2′):

wherein, * indicates an asymmetric carbon atom,is stereoselectively protected with a tert-butoxycarbonyl group, in amixture of the compound (2′) and optically active nipecotic acidrepresented by the following formula (3′):

wherein, * means the same as the above,to obtain optically active 1-(tert-butoxycarbonyl)nipecotamiderepresented by the following formula (8):

wherein, * means the same as the above,and the compound (8) is separated from the compound (3′).

When the protection with a t-butoxycarbony group is carried out by aconventional method, the optically active nipecotic acid represented bythe formula (3′) is also protected with a t-butoxycarbony group; as aresult, an expensive butoxycarbonylating agent is wasted. Therefore, thepresent inventors found that only the compound (2′) could be highlyselectively t-butoxycarbonylated by adjusting the pH in bilayer of anorganic solvent and water.

Di-tert-butyl dicarbonate is preferred as the butoxycarbonylating agent.The use amount of the butoxycarbonylating agent is preferably 0.5 to 5equivalents, more preferably 0.8 to 2 equivalents, relative to thecompound (2′).

In the present step, the pH is adjusted by further adding a base.

The base includes metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, barium hydroxide and magnesiumhydroxide; metal carbonates such as lithium carbonate, sodium carbonateand potassium carbonates; metal hydrogen carbonate salts such as lithiumhydrogen carbonate, sodium hydrogen carbonate and potassium hydrogencarbonate; and metal alkoxides such as lithium methoxide, lithiumethoxide, sodium methoxide, sodium ethoxide, potassium methoxide,potassium ethoxide and potassium tert-butoxide. The base is preferablylithium hydroxide, sodium hydroxide, potassium hydroxide, lithiumcarbonate, sodium carbonate and potassium carbonate, more preferablysodium hydroxide and potassium hydroxide.

The use amount of the base is preferably 0.1 to 10 times by mole, morepreferably 0.3 to 5 times by mole, relative to the compound (2′).

The reaction of the present step is carried out by mixing an organicsolvent with the aqueous solution containing the mixture of thecompounds (2′) and (3′).

The organic solvent includes alcoholic solvents such as methanol,ethanol and isopropanol; ether type solvents such as tetrahydrofuran,1,4-dioxane and ethylene glycol dimethyl ether; ester solvents such asethyl acetate and isopropyl acetate; hydrocarbon solvents such asbenzene, toluene and hexane; ketone solvents such as acetone and methylethyl ketone; nitrile solvents such as acetonitrile, propionitrile andbenzonitrile; halogen type solvents such as methylene chloride andchloroform; amide solvents such as N,N-dimethylformamide andN,N-dimethylacetoamide; sulfoxide solvents such as dimethyl sulfoxide;urea solvents such as dimethylpropylene urea; and triamide phosphonatesolvents such as triamide hexamethylphosphonate. One of the solvents maybe singly used, or two or more solvents may be used in combination.

The organic solvent is preferably tetrahydrofuran, 1,4-dioxane andisopropanol, more preferably tetrahydrofuran. If the aqueous solutioncontaining the mixture of the compounds (2′) and compound (3′) and theorganic solvent are not separated into two layers, an inorganic saltsuch as sodium chloride, lithium chloride or sodium sulfate may befurther added for layer separation.

The use amount of the organic solvent is preferably 50 times or less byweight, more preferably 20 times or less by weight, relative to thecompound (2′).

The reaction temperature of the present step is preferably from −20 to80° C., more preferably from 0 to 50° C. Although the reaction time ofthe step is not particularly limited, the time is preferably from 30minutes to 24 hours, more preferably from 1 to 6 hours.

Though the addition method and addition order of the compound (2′), thebase, the butoxycarbonylating agent and the reaction solvent upon thereaction are not particularly limited, the butoxycarbonylating agent andthe base may be preferably added at the same time to the solution of thecompound (2′) for the purpose of adjusting the pH.

The treatment after the reaction involves adding a general extractionsolvent such as ethyl acetate, diethyl ether, methylene chloride,toluene or hexane to the reaction mixture for extraction operation. Insuch a case, although the compound (3′) is hardly extracted to theorganic layer due to high water solubility, the pH of the water layer isadjusted to preferably 7 or higher, more preferably from 8 to 13 to beable to completely separate the compound (3′) into the organic layer.The reaction solvent and extraction solvent are evaporated from theresulting extract by an operation such as heating under reduced pressureto obtain the target compound. Alternatively, the organic solvent isevaporated under reduced pressure from the solution after the reaction,or a poor solvent such as hexane or methylcyclohexane is added tothereby be capable of precipitating the target compound as crystal. Thecrystal may be filtered off and isolated by pressure filtration, vacuumfiltration or centrifugal separation.

Although the target compound obtained by the method has a purity enoughto be usable in the following step, the purity may also be furtherimproved by a general purifying means such as crystallization,fractional distillation or column chromatography for the purpose offurther improving the yield in the following step or the purity of acompound obtained in the following step.

Step 7

In the present step, optically active1-(tert-butoxycarbonyl)-3-aminopiperidine or salt thereof, representedby the following formula (9):

wherein, * means the same as the above,is produced by Hofmann rearrangement at the amide group of the opticallyactive 1-(tert-butoxycarbonyl)nipecotamide which is produced in Step 6and is represented by the following formula (8):

wherein, * means the same as the above.

In the present step, the compound (8) is reacted with an oxidizing agentand a base to carry out Hofmann rearrangement.

The oxidizing agent includes, for example, chlorine, bromine and sodiumhypochlorite. The oxidizing agent is preferably sodium hypochlorite, andaqueous sodium hypochlorite solution may be preferably used from theviewpoints of storage stability and easiness of handling. Theconcentration of the aqueous solution is preferably from 5 to 30% byweight. The use amount of the oxidizing agent is preferably 1 to 10times by mole, more preferably 1 to 3 times by mole, relative to thecompound (8).

The base includes, for example, metal hydroxides such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide andmagnesium hydroxide; metal alkoxides such as lithium methoxide, lithiumethoxide, sodium methoxide, sodium ethoxide, potassium methoxide,potassium ethoxide and potassium tert-butoxide. The base is preferablylithium hydroxide, sodium hydroxide and potassium hydroxide.

The use amount of the base is preferably 0.5 to 30 times by mole, morepreferably 3 to 15 times by mole, relative to the compound (8).

The reaction temperature of the present step is preferably from −20 to100° C., more preferably from −5 to 70° C.

The reaction time of the step is preferably from 30 minutes to 24 hours,more preferably from 1 to 12 hours.

Water is preferred as the reaction solvent of the step. In addition, anorganic solvent may be further coexisted in order to promote thereaction.

The use amount of the solvent is preferably 50 times or less by weight,more preferably 20 times or less by weight, relative to the compound(8).

The addition method and addition order of the compound (8), theoxidizing agent, the base and the reaction solvent upon the reaction arenot particularly limited; however, the oxidizing agent may be addeddropwise lastly from the viewpoint of improving the yield.

General treatment for obtaining a product from a reaction mixture may becarried out as the treatment after the reaction. For example, water or,as necessary, an aqueous acid solution such as hydrochloric acid ordiluted sulfuric acid is added to the reaction mixture after completionof the reaction for neutralization, and extraction may be carried outusing a general extraction solvent such as ethyl acetate, diethyl ether,methylene chloride, toluene, hexane or the like. The reaction solventand extraction solvent are evaporated from the resulting extract by anoperation such as heating under reduced pressure to obtain the targetcompound. Although the thus obtained target compound has purity enoughto be usable in the following step, the purity may also be furtherimproved by a general purifying means such as crystallization,fractional distillation or column chromatography for the purpose offurther improving the yield in the following step or the purity of acompound obtained in the following step.

Step 8

In the present step, optically active 3-aminopiperidine or salt thereof,represented by the following formula (7):

wherein, * indicates an asymmetric carbon atom,is produced by treating optically active1-(tert-butoxycarbonyl)-3-aminopiperidine or salt thereof which isproduced in Step 7 and is represented by the following formula (9):

wherein, * means the same as the above,with an acid for deprotection at 1-position.

The acid is not particularly limited, and the example thereof includesmineral acids such as hydrogen chloride, hydrogen bromide, sulfuric acidand nitric acid, and sulfonic acids such as trifluoromethane sulfonicacid, p-toluenesulfonic acid and methanesulfonic acid. The acid ispreferably hydrogen chloride, hydrobromic acid and sulfuric acid, morepreferably hydrogen chloride. Although the acid may be used directly,the solution prepared by dissolving the acid in methanol, ethanol,isopropanol, 1,4-dioxane or water is rather preferred.

The use amount of the acid is preferably 50 times or less by mole, morepreferably 1 to 20 times by mole, relative to the compound (9). Thereaction temperature of the present step is preferably from 30 to 200°C., more preferably from 50° C. to 140° C. Although the reaction time ofthe reaction is not particularly limited, the time is preferably from 1to 40 hours, more preferably from 5 to 30 hours.

The reaction solvent includes water; alcoholic solvents such asmethanol, ethanol and isopropanol; and ether type solvents such astetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether. One ofthe solvents may be singly used, or two or more solvents may be used incombination. When two or more solvents are used in combination, themixing ratio is not particularly limited. The reaction solvent isalcoholic solvents such as methanol, ethanol and isopropanol.

The addition method and addition order of the compound (9), the acid andthe reaction solvent upon the reaction are not particularly limited.

General treatment for obtaining a product from a reaction mixture may becarried out as the treatment after the reaction. For example, water or,as necessary, an aqueous alkaline solution such as an aqueous sodiumhydroxide solution or aqueous potassium carbonate solution is added tothe reaction mixture after completion of the reaction forneutralization, and extraction may be carried out using a generalextraction solvent such as ethyl acetate, diethyl ether, methylenechloride, toluene, hexane or the like. The reaction solvent andextraction solvent are evaporated from the resulting extract by anoperation such as heating under reduced pressure to obtain the targetcompound.

Although thus obtained target compound has purity enough to be usable inthe following step, the purity may also be further improved by a generalpurifying means such as crystallization, fractional distillation orcolumn chromatography for the purpose of further improving the yield inthe following step or the purity of a compound obtained in the followingstep.

Alternatively, the reaction solvent may be evaporated from the reactionmixture by an operation such as heating under reduced pressure toisolate the target compound as a salt of the compound (7) and the acidor to crystallize the target compound for the purpose of furtherimproving the purity.

The solvent for carrying out crystallization preferably includesalcoholic solvents such as methanol, ethanol and isopropanol; ether typesolvents such as tetrahydrofuran, 1,4-dioxane and ethylene glycoldimethyl ether; ester solvents such as ethyl acetate and isopropylacetate; hydrocarbon solvents such as benzene, toluene, xylene andhexane; and halogen type solvents such as methylene chloride, chloroformand chlorobenzene. One of the solvents may be singly used, or two ormore solvents may be used in combination. The solvent is more preferablymethanol, ethanol, ethyl acetate, toluene, xylene, chlorobenzene and thelike.

Moreover, optically active 3-aminopiperidine or salt thereof can beobtained also by the following scheme. Each step is sequentiallydescribed below.

Step 9

In the present step, optically active 1-(benzyl)amino piperidine or saltthereof represented by the following formula (10):

wherein, * indicates an asymmetric carbon atom,is produced by Hofmann rearrangement at the amide group of the opticallyactive 1-(benzyl)nipecotamide which is produced in Step 1 andrepresented by the following formula (2″):

wherein, * means the same as the above.

In the present step, the compound (2″) is reacted with an oxidizingagent and a base to carry out the Hofmann rearrangement.

The oxidizing agent includes, for example, chlorine, bromine and sodiumhypochlorite. The oxidizing agent is preferably sodium hypochlorite, andthe aqueous solution thereof may be used from the viewpoints of storagestability and easiness of handling. The concentration of the aqueoussolution is preferably from 5 to 30% by weight.

The use amount of the oxidizing agent is preferably 1 to 10 times bymole, more preferably 1 to 3 times by mole, relative to the compound(8).

The base includes, for example, metal hydroxides such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide andmagnesium hydroxide; metal alkoxides such as lithium methoxide, lithiumethoxide, sodium methoxide, sodium ethoxide, potassium methoxide,potassium ethoxide and potassium tert-butoxide. The base is preferablylithium hydroxide, sodium hydroxide and potassium hydroxide.

The use amount of the base is preferably 0.5 to 30 times by mole, morepreferably 3 to 15 times by mole, relative to the compound (2″). Thereaction temperature of the present step is preferably from −20 to 100°C., more preferably from −5 to 70° C.

The reaction time of the step is preferably from 30 minutes to 24 hours,more preferably from 1 to 12 hours.

The reaction solvent of the step is not particularly limited, and waterand a general organic solvent can be used. Among them, water ispreferred. The organic solvent to be used includes alcoholic solventssuch as methanol, ethanol and isopropanol; ether type solvents such astetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether; estersolvents such as ethyl acetate and isopropyl acetate; hydrocarbonsolvents such as benzene, toluene and hexane; ketone solvents such asacetone and methyl ethyl ketone; nitrile solvents such as acetonitrileand propionitrile; halogen type solvents such as methylene chloride andchloroform; amide solvents such as N,N-dimethylformamide andN,N-dimethylacetoamide; sulfoxide solvents such as dimethyl sulfoxide;urea solvents such as dimethylpropylene urea; and triamide phosphonatesolvents such as triamide hexamethylphosphonate. One of the solvents maybe singly used, or two or more solvents may be used in combination. Whentwo or more solvents are used in combination, the mixing ratio is notparticularly limited.

The use amount of the solvent is preferably 50 times or less by weight,more preferably 20 times or less by weight, relative to the compound(2″).

The addition method and addition order of the compound (2″), theoxidizing agent, the base and the reaction solvent upon the reaction arenot particularly limited, and the oxidizing agent may be added dropwiselastly from the viewpoint of improving the yield.

General treatment for obtaining a product from a reaction mixture may becarried out as the treatment after the reaction. For example, water or,as necessary, an aqueous acid solution such as hydrochloric acidsolution or diluted sulfuric acid is added to the reaction mixture aftercompletion of the reaction for neutralization, and extraction may becarried out using a general extraction solvent such as ethyl acetate,diethyl ether, methylene chloride, toluene, hexane or the like. Thereaction solvent and extraction solvent are evaporated from theresulting extract by an operation such as heating under reduced pressureto obtain a target substance.

Although the thus obtained target compound has purity enough to beusable in the following step, the purity may also be further improved bya general purifying means such as crystallization, fractionaldistillation or column chromatography for the purpose of furtherimproving the yield in the following step or the purity of a compoundobtained in the following step.

Step 10

In the present step, optically active 3-aminopiperidine or salt thereofrepresented by the following formula (7):

wherein, * indicates an asymmetric carbon atom,is produced by reacting the optically active 1-(benzyl)amino piperidineor salt thereof which is produced in Step 9 and represented by thefollowing formula (10):

wherein, * means the same as the above,with a hydrogen source in the presence of a catalyst for deprotection at1-position by additional hydrogen decomposition.

The hydrogen source is not particularly limited, and the example thereofincludes hydrogen, formic acid and ammonium formate, preferablyhydrogen.

The catalyst is not particularly limited, and the example thereofincludes palladium, palladium hydroxide, platinum, rhodium andruthenium. The catalyst is preferably palladium and palladium hydroxide.The catalyst may be directly used, or a supported catalyst on activatedcharcoal, silica gel, alumina or the like may also be used.

In the present reaction, an acid may be added for the implementation ofthe reaction.

The acid is not particularly limited, and the example thereof includesmineral acids such as hydrogen chloride, hydrogen bromide, sulfuric acidand nitric acid; sulfonic acids such as trifluoromethane sulfonic acid,p-toluenesulfonic acid and methanesulfonic acid; and carboxylic acidssuch as acetate, propionic acid and butyric acid. The acid is preferablyhydrogen chloride, hydrobromic acid and sulfuric acid, more preferablyhydrogen chloride. Although the acid may be used directly, the aqueoussolution thereof is preferably used.

The use amount of the acid is preferably 50 times or less by mole, morepreferably 1 to 20 times by mole, relative to the compound (10).

The reaction temperature of the present step is preferably from 0° C. to150° C., more preferably from 10° C. to 100° C.

Although the reaction time of the reaction is not particularly limited,the time is preferably from 1 to 40 hours, more preferably from 5 to 30hours.

The solvent of the present reaction includes water; alcoholic solventssuch as methanol, ethanol and isopropanol; ether type solvents such astetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether; estersolvents such as ethyl acetate and isopropyl acetate; hydrocarbonsolvents such as benzene, toluene, xylene and hexane; ketone solventssuch as acetone and methyl ethyl ketone; nitrile solvents such asacetonitrile, propionitrile and benzonitrile; halogen type solvents suchas methylene chloride, chloroform and chlorobenzene; amide solvents suchas N,N-dimethylformamide and N,N-dimethylacetoamide; sulfoxide solventssuch as dimethyl sulfoxide; urea solvents such as dimethylpropyleneurea; and triamide phosphonate solvents such as triamidehexamethylphosphonate. One of the solvents may be singly used, or two ormore solvents may be used in combination. The solvent is preferablywater; alcoholic solvents such as methanol and isopropanol.

The addition method and addition order of the compound (10), thecatalyst, the hydrogen source and the reaction solvent upon the reactionare not particularly limited.

General treatment for obtaining a product from a reaction mixture may becarried out as the treatment after the reaction. For example, water or,as necessary, an aqueous alkaline solution such as an aqueous sodiumhydroxide solution or aqueous potassium carbonate solution is added tothe reaction mixture after completion of the reaction forneutralization, and extraction may be carried out using a generalextraction solvent such as ethyl acetate, diethyl ether, methylenechloride, toluene, hexane or the like. The reaction solvent andextraction solvent are evaporated from the resulting extract by anoperation such as heating under reduced pressure to obtain the targetcompound.

Although the thus obtained target compound has purity enough to beusable in the following step, the purity may also be further improved bya general purifying means such as crystallization, fractionaldistillation or column chromatography for the purpose of furtherimproving the yield in the following step or the purity of a compoundobtained in the following step.

Alternatively, the reaction solvent may be evaporated from the reactionmixture by an operation such as heating under reduced pressure toisolate the target compound as a salt of the compound (7) and the acidor to further crystallize the compound for the purpose of improving thepurity.

The solvent for carrying out crystallization preferably includesalcoholic solvents such as methanol, ethanol and isopropanol; ether typesolvents such as tetrahydrofuran, 1,4-dioxane and ethylene glycoldimethyl ether; ester solvents such as ethyl acetate and isopropylacetate; hydrocarbon solvents such as benzene, toluene, xylene andhexane; and halogen type solvents such as methylene chloride, chloroformand chlorobenzene. One of the solvents may be singly used, or two ormore solvents may be used in combination. The solvent is more preferablymethanol, ethanol, ethyl acetate, toluene, xylene, chlorobenzene and thelike.

EXAMPLES

The present invention is described in more detail by the followingexamples; however, the invention is by no means limited to the examples.

Example 1 Selective hydrolysis of (R)- or (S)-1-nipecotamide in racemate

Each microorganism shown in Tables 1 and 2 was inoculated in a medium (8ml, glycerol 1.0%, peptone 0.5%, malt extract 0.3%, yeast extract 0.3%,isovaleronitrile 0.1%, pH 7.0) sterilized in vitro, and stirred andcultivated at 30° C. for 72 hours. After completion of the cultivation,the bacterial cells were collected by centrifugal separation, andsuspended in 100 mM phosphate buffer (1 ml, pH 7.0). The bacterial cellsuspension (0.1 ml) was mixed with 100 mM phosphate buffer containing0.2% of racemic 1-benzylnipecotamide (0.1 ml, pH 7.0), and the mixturewas shaken at 30° C. for 24 hours. After completion of the reaction,solid substance was removed by centrifugal separation, and then thesubstrate and product in the reaction mixture were analyzed by highperformance liquid chromatography to determine the conversion rate (%)and optical purity (% ee). The results are shown in Tables 1 and 2. TheKNK-J915 strain is deposited under the accession number FERM BP-10739with International Patent Organism Depositary, National Institute ofAdvanced Industrial Science and Technology (Zip Code 305-8566 Chuou No.6, 1-1-1 Higashi Tsukuba City Ibaraki Prefecture).

Conversion rate(%)=amount of product/(amount of substrate+amount ofproduct)×100

Optical purity(%ee)=(A−B)/(A+B)×100(A and B represent the amount ofcorresponding enantiomers, and A>B)

High Performance Liquid Chromatographic Analysis Conditions

Analysis of Conversion Rate

Column: YMC-A303 (4.6 mmφ×250 mm, manufactured by YMC Inc.), Eluent: 20mM phosphoric acid aqueous solution (pH 2.5)/acetonitrile=9/1, Flowrate: 1.0 ml/minute, Column temperature: 30° C., Measuring wavelength:210 nm

Analysis of Optical Purity

Column: CHIRALPAK AD-RH (4.6 mmφ×150 mm, manufactured by Daicel ChemicalIndustries, Ltd.), Eluent: 20 mM phosphate buffer (pH8.0)/acetonitrile=7/3, Flow rate: 0.5 ml/minute, Column temperature:room temperature, Measuring wavelength: 210 nm

TABLE 1 Substrate Product Conversion Optical Optical Strain name rate(%) purity (% ee) purity (% ee) Achromobacter xylosoxidans 48.8 95.397.8 susp. xylosoxidans NBRC 13495 Cupriavidus sp. KNK-J915 52.0 99.992.3 FERM BP-10739 Pseudomonas chlororaphis 66.8 95.9 47.6 NBRC 3904Rhodococcus erythropolis 51.0 97.9 93.9 IAM 1440

TABLE 2 Substrate Product Conversion Optical Optical Strain name rate(%) purity (% ee) purity (% ee) Brevibacterium iodinum 69.7 98.0 42.6NBRC 3558 Pseudomonas fragi 59.4 97.2 66.3 NBRC 3458 Pectobacterium 57.198.2 73.7 carotovorum subsp. carotovorum NBRC 12380 Staphylococcusepidermidis 52.2 92.6 84.7 JCM 2414

Example 2 Method for producing (R)-1-benzylnipecotamide

Cupriavidus sp. KNK-J915 stain (FERM BP-10739) was inoculated in amedium (glycerol 1.0%, peptone 0.5%, malt extract 0.3%, yeast extract0.3%, isovaleronitrile 0.1%, pH 7.0) sterilized in a Sakaguchi flask,and stirred and cultivated at 30° C. for 72 hours. After completion ofthe cultivation, the bacterial cells were collected by centrifugalseparation, and suspended in 100 mM phosphate buffer (pH 7.0) to obtaina 20-fold concentrated bacterial cell suspension. To the bacterial cellsuspension (100 ml), racemic 1-benzylnipecotamide (5 g) was added. ThepH of the solution was adjusted to 7 using NaOH, and then the mixturewas shaken at 30° C. for 60 hours. After completion of the reaction,solid substance such as bacterial cells was removed by centrifugalseparation from the reaction mixture, and the pH of the mixture wasadjusted to 10.0 using NaOH. The mixture was stirred at room temperaturefor 1 hour, and then precipitated crystal was filtrated to obtain 2.4 gof (R)-1-benzylnipecotamide. The compound was analyzed by the method ofExample 1; as a result, the optical purity was 99.8% ee.

Example 3 Selective hydrolysis of R-enantiomer in racemic nipecotamide

Cupriavidus sp. KNK-J915 strain (FERM BP-10739) was cultivated by themethod of Example 1 to prepare a bacterial cell suspension. Thebacterial cell suspension (0.1 ml) was mixed with 100 mM phosphatebuffer containing 1.0 to 5.0% of racemic nipecotamide (0.1 ml, pH 7.0),and the mixture was shaken at 30° C. for 35 hours. After completion ofthe reaction, solid substance such as bacterial cells was removed bycentrifugal separation, and then a substrate and a product in thereaction mixture were reacted with benzyl chlorocarbonate forderivatization. The resulting derivative was analyzed by highperformance liquid chromatography to determine the conversion rate (%)and optical purity (ee %). The results are listed in Table 3.

High Performance Liquid Chromatographic Analysis Conditions

Analysis of Conversion Rate

Column: YMC-A303 (4.6 mmφ×250 mm, manufactured by YMC Inc.),

Eluent: 20 mM phosphoric acid aqueous solution (pH2.5)/acetonitrile=7/3, Flow rate: 1.0 ml/minute, Column temperature: 35°C., Measuring wavelength: 210 nm

Analysis of Optical Purity

Column: CHIRALPAK AD-RH (4.6 mmφ×150 mm, manufactured by Daicel ChemicalIndustries, Ltd.), Eluent: 20 mM phosphate buffer (pH2.5)/acetonitrile=7/3, Flow rate: 0.5 ml/minute, Column temperature:room temperature, Measuring wavelength: 210 nm

TABLE 3 Concentration Substrate Product of racemic Conversion OpticalOptical nipecotamide rate (%) purity (% ee) purity (% ee) 1.0 66.8 95.947.6 3.0 64.8 98.7 53.7 5.0 57.1 98.2 73.7

Example 4 Selective hydrolysis of S-enantiomer in racemic nipecotamide

Cupriavidus sp. KNK-J915 strain (FERM BP-10739) was cultivated by themethod of Example 2 to obtain a 20-fold concentrated bacterial cellsuspension. To the bacterial cell suspension (100 ml), racemicnipecotamide (19.9 g) was added. After the pH of the mixture wasadjusted to 7 using NaOH, the mixture was shaken at 30° C. for 60 hours.After completion of the reaction, the reaction mixture was heat-treatedat 70° C. for 30 minutes, and solid substance such as bacterial cellswas removed by centrifugal separation. The substrate and product in thereaction mixture were analyzed by the method of Example 3; as a result,the conversion rate was 52.7%, the optical purity of (R)-nipecotamidewas 98.8% ee and the optical purity of (S)-nipecotamide was 88.1% ee.

Example 5 Method for producing (R)-1-(tert-butoxycarbonyl) nipecotamide

To the reaction mixture obtained in Example 4, THF (40 ml) was added,and di-tert-butyl dicarbonate (37.2 g, 2.3 equivalents) was addedthereto. The pH of the reaction mixture was adjusted to 10.0 using NaOH.The reaction mixture was stirred for 1 hour at room temperature, andthen the precipitated crystal was filtered off to obtain(R)-1-(tert-butoxycarbonyl)nipecotamide as white crystal (15.6 g, yield:93%). The crystal was analyzed by the method of Example 3; as a result,the optical purity was 99.8% ee.

¹H NMR (400 MHz, CDCl₃): δ 5.36 (brs, 2H), 3.94-3.08 (m, 5H), 1.96-1.36(m, 13H)

Example 6 Method for producing (R)-1-(tert-butoxycarbonyl) nipecotamide

To the reaction mixture obtained in Example 4, THF (40 ml) was added,and di-tert-butyl dicarbonate (16.1 g, 1.0 equivalent) was addedthereto. The pH of the reaction mixture was kept to 7.0 to 8.0. Thereaction mixture was stirred for 3 hours at room temperature to obtain asolution containing (R)-1-(tert-butoxy carbonyl)nipecotamide (15.6 g,yield: 93%).

Example 7 Method for producing (R)-1-(tert-butoxycarbonyl) nipecotamide

To the reaction mixture obtained in Example 4, THF (40 ml) was added,and di-tert-butyl dicarbonate (16.1 g, 1.0 equivalent) was addedthereto. The pH of the reaction mixture was kept to 5.0 to 6.0. Thereaction mixture was stirred for 3 hours at room temperature to obtain asolution containing (R)-1-(tert-butoxy carbonyl)nipecotamide (3.5 g,yield: 21%).

Example 8 Method for producing (R)-1-(tert-butoxycarbonyl) nipecotamide

To the reaction mixture obtained in Example 4, THF (40 ml) was added,and di-tert-butyl dicarbonate (16.1 g, 1.0 equivalent) was addedthereto. The pH of the reaction mixture was kept 5.0 to 7.0. Thereaction mixture was stirred for 2 hours at room temperature to obtain asolution containing (R)-1-(tert-butoxycarbonyl) nipecotamide (1.9 g,yield: 11%).

Example 9 Method for producing (R)-1-(tert-butoxycarbonyl) nipecotamide

To the reaction mixture obtained in Example 4, tert-butyl dicarbonate(16.1 g, 1.0 equivalent) was added. The pH of the reaction mixture waskept from 7.0 to 8.0. The reaction mixture was stirred for 3 hours atroom temperature to obtain a solution containing(R)-1-(tert-butoxycarbonyl)nipecotamide (6.6 g, yield: 39%).

Example 10 Method for producing (R)-1-benzoylnipecotamide

Concentrated sulfuric acid is added to the reaction mixture obtained inExample 4 (amount: 10 g, net weight of (R)-nipecotamide: 1 g) to adjustthe pH to 9. Benzoyl chloride (3.5 g, 2.5 equivalents) was slowly addeddropwise, and the pH of the reaction mixture was kept from 7 to 9 by a30% aqueous sodium hydroxide solution. After completion of the dropwiseaddition, the solution was stirred at 15° C. for 3 hours to obtain asolution containing the title compound (1.6 g, yield: 88%).

¹H NMR (400 MHz, CDCl₃): δ 7.45-7.36 (m, 5H), 6.70 (brs, 2H), 5.56 (brd,1H), 4.17-3.75 (m, 2H), 3.56-3.25 (m, 2H), 2.18-1.88 (m, 2H), 1.64-1.38(m, 2H)

Example 11 Method for producing (R)-1-(p-methylbenzoyl) nipecotamide

Concentrated sulfuric acid is added to the reaction mixture obtained inExample 4 (amount: 30 g, net weight of (R)-nipecotamide: 3 g) to adjustthe pH to 9. To the mixture, p-Methylbenzoyl chloride (8.0 g, 2.2equivalents) was slowly added dropwise, and the pH of the reactionmixture was kept from 7 to 9 by a 30% aqueous sodium hydroxide solution.After completion of the dropwise addition, the solution was stirred at15° C. for 3 hours and the precipitated crystal was filtered off. Thecrystal was dried under reduced pressure to obtain the title compound aswhite crystal (4.4 g, yield: 76%).

¹H NMR (400 MHz, CDCl₃): δ 7.42-7.22 (m, 4H), 6.56 (brs, 2H), 5.60 (brd,1H), 4.18-3.18 (m, 4H), 2.18-1.40 (m, 4H)

Example 12 Method for producing (R)-1-(p-chlorobenzoyl) nipecotamide

Concentrated sulfuric acid is added to the reaction mixture obtained inExample 4 (amount: 30 g, net weight of (R)-nipecotamide: 3 g) to adjustthe pH to 9. To the mixture, p-Methylbenzoyl chloride (9.0 g, 2.2equivalents) was slowly added dropwise, and the pH of the reactionmixture was kept from 7 to 9 by a 30% aqueous sodium hydroxide solution.After completion of the dropwise addition, the solution was stirred at15° C. for 3 hours, and the precipitated crystal was filtered off. Thecrystal was dried under reduced pressure to obtain the title compound aswhite crystal (6.2 g, yield: 99%).

¹H NMR (400 MHz, CDCl₃): δ 7.50-7.22 (m, 4H), 6.68 (brd, 2H), 5.80 (brs,1H), 4.18-3.36 (m, 4H), 2.60-1.46 (m, 7H)

Example 13 Method for producing (R)-1-(p-methylbenzoyl)-3-aminopiperidine

To the white crystal (4.0 g) obtained in Example 11, water (20 ml),sodium hydroxide (1.3 g, 2 equivalents) and aqueous sodium hypochloritesolution (10.2 g, 1 equivalent) were added. The mixture was stirred at15 to 40° C. for 2 hours to obtain a pale yellow aqueous solution (34.7g). To 11.0 g of the subdivided solution, isopropanol (5 ml) and sodiumchloride (1 g) were added. The mixture was stirred at 60° C. for 10minutes. The water layer was separated, and the solvent was evaporatedunder reduced pressure to obtain the title compound as yellow oil (0.72g, yield: 64%).

¹H NMR (400 MHz, CDCl₃): δ 7.42-7.18 (m, 4H), 4.58-4.22 (m, 1H),3.84-3.46 (m, 1H), 3.08-2.66 (m, 3H), 2.44-1.24 (m, 7H)

Example 14 Method for producing (R)-1-(p-chlorobenzoyl)-3-aminopiperidine

To the white crystal (5.7 g) obtained in Example 11, water (30 ml),sodium hydroxide (1.7 g, 2 equivalents) and aqueous sodium hypochloritesolutions (13.4 g, 1 equivalent) were added. The mixture was stirred at15 to 40° C. for 2 hours to obtain a pale yellow aqueous solution (54.1g). To 10.3 g of the subdivided solution, isopropanol (5 ml) and sodiumchloride (1 g) were added. The mixture was stirred at 60° C. for 10minutes. The water layer was removed, and the solvent was evaporatedunder reduced pressure to obtain the title compound as yellow oil (0.87g, yield: 90%).

¹H NMR (400 MHz, CDCl₃): δ 7.42-7.18 (m, 4H), 4.52-4.16 (m, 1H),3.80-3.18 (m, 1H), 3.06-2.64 (m, 3H), 2.18-1.22 (m, 4H)

Example 15 Method for producing(R)-1-(p-methylbenzoyl)-3-(benzoylamino)piperidine

Benzoyl chloride (0.15 g) was added to the aqueous solution of(R)-1-(p-methylbenzoyl)-3-aminopiperidine obtained in Example 13(amount: 3 g), and the pH of the mixture was kept from 8.0 to 9.0 usingsodium hydroxide. The mixture was stirred at 15° C. for 3 hours.Chlorobenzene (3 ml) and sodium chloride (0.5 g) were added thereto, andthen the mixture was stirred at 90° C. for 10 minutes. The water layerwas removed, and the solvent was evaporated under reduced pressure toobtain the title compound as yellow crystal (0.33 g, yield: 73%).

¹H NMR (400 MHz, CDCl₃): δ 7.58-7.14 (m, 9H), 4.22 (brs, 1H), 3.60 (brs,1H), 2.37 (s, 3H), 2.28-1.52 (m, 4H)

Example 16 Method for producing(R)-1-(p-chlorobenzoyl)-3-(benzoylamino)piperidine

Benzoyl chloride (0.15 g) was added to the aqueous solution of(R)-1-(p-chlorobenzoyl)-3-aminopiperidine obtained in Example 14(amount: 3 g), and the pH of the mixture was kept from 8.0 to 9.0 usingsodium hydroxide. The mixture was stirred at 15° C. for 3 hours, andchlorobenzene (3 ml) and sodium chloride (0.5 g) were added thereto. Themixture was stirred at 90° C. for 10 minutes. The water layer wasremoved, and the solvent was evaporated under reduced pressure to obtainthe title compound as yellow crystal (0.42 g, yield: 100%).

¹H NMR (400 MHz, CDCl₃): δ 7.90-7.16 (m, 9H), 6.04 (brs, 1H), 4.32-3.18(m, 5H), 2.18-1.40 (m, 4H)

Example 17 Method for producing(R)-1-(p-methylbenzoyl)-3-(p-methylbenzoylamino)piperidine

To the aqueous solution of (R)-1-(p-methylbenzoyl)-3-amino piperidineobtained in Example 13 (amount: 3 g), p-Methylbenzoyl chloride (0.16 g)was added. The pH of the mixture was kept from 8.0 to 9.0 using sodiumhydroxide. The mixture was stirred at 15° C. for 3 hours, and theprecipitated crystal was filtered off. The crystal was dried underreduced pressure to obtain the title compound as white crystal (0.28 g,yield: 59%).

¹H NMR (400 MHz, CDCl₃): δ 7.82-7.12 (m, 8H), 6.12 (brs, 1H), 4.21 (s,2H), 3.59 (s, 2H), 3.35 (s, 1H), 2.39 (s, 3H), 2.36 (s, 3H), 2.10-1.40(m, 4H)

Example 18 Method for producing(R)-1-(p-chlorobenzoyl)-3-(p-methylbenzoylamino)piperidine

To the aqueous solution of (R)-1-(p-chlorobenzoyl)-3-amino piperidineobtained in Example 14 (amount: 3 g), p-Methylbenzoyl chloride (0.16 g)was added. The pH of the mixture was kept from 8.0 to 9.0 using sodiumhydroxide. The mixture was stirred at 15° C. for 3 hours, and theprecipitated crystal was filtered off. The crystal was dried underreduced pressure to obtain the title compound as white crystal (0.28 g,yield: 66%).

¹H NMR (400 MHz, CDCl₃): δ 7.80-7.16 (m, 8H), 6.08 (brs, 1H), 4.36-3.12(m, 5H), 2.40 (s, 3H), 2.22-1.42 (m, 4H)

Example 19 Method for producing(R)-1-(p-methylbenzoyl)-3-(p-chlorobenzoylamino)piperidine

To the aqueous solution of (R)-1-(p-methylbenzoyl)-3-amino piperidineobtained in Example 13 (amount: 3 g), p-chlorobenzoyl chloride (0.18 g)was added. The pH of the mixture was kept from 8.0 to 9.0 using sodiumhydroxide. The mixture was stirred at 15° C. for 3 hours, andchlorobenzene (3 ml) and sodium chloride (0.5 g) were added thereto. Themixture was stirred at 90° C. for 10 minutes. The water layer wasremoved, and the solvent was evaporated under reduced pressure to obtainthe title compound as yellow crystal (0.42 g, yield: 84%).

¹H NMR (400 MHz, CDCl₃): δ 7.88-7.08 (m, 8H), 4.21 (brs, 1H), 3.82-3.18(m, 3H), 2.37 (s, 3H), 2.16-1.42 (m, 4H)

Example 20 Method for producing(R)-1-(p-chlorobenzoyl)-3-(p-chlorobenzoylamino)piperidine

To the aqueous solution of (R)-1-(p-chlorobenzoyl)-3-amino piperidineobtained in Example 14 (amount: 3 g), p-chlorobenzoyl chloride (0.15 g)was added. The pH of the mixture was kept from pH 8.0 to 9.0 usingsodium hydroxide. The mixture was stirred at 15° C. for 3 hours, andchlorobenzene (3 ml) and sodium chloride (0.5 g) were added. The mixturewas stirred at 90° C. for 10 minutes. The water layer was removed, andthe solvent was evaporated under reduced pressure to obtain the titlecompound as yellow crystal (0.16 g, yield: 36%).

¹H NMR (400 MHz, CDCl₃): δ 7.82-7.20 (m, 8H), 6.02 (brs, 1H), 4.36-3.08(m, 5H), 2.22-1.22 (m, 4H)

Example 21 Method for producing(R)-1-(p-methylbenzoyl)-3-(tert-butoxycarbonylamino)piperidine

Potassium carbonate (0.15 g) and di-tert-butyl dicarbonate (0.23 g) wereadded to the aqueous solution of (R)-1-(p-methylbenzoyl)-3-aminopiperidine obtained in Example 13 (amount: 3 g). Themixture was stirred at 15° C. for 3 hours, and chlorobenzene (3 ml) andsodium chloride (0.5 g) were added. The mixture was stirred at 90° C.for 10 minutes. The water layer was removed, and the solvent wasevaporated under reduced pressure to obtain the title compound as yellowoil (0.31 g, yield: 69%).

¹H NMR (400 MHz, CDCl₃): δ 7.38-7.18 (m, 4H), 4.68 (brs, 1H), 3.80-3.06(m, 4H), 2.36 (s, 3H), 1.98-1.26 (m, 13H)

Example 22 Method for producing(R)-1-(p-chlorobenzoyl)-3-(tert-butoxycarbonylamino)piperidine

Potassium carbonate (0.15 g) and di-tert-butyl dicarbonate (0.23 g) wereadded to the aqueous solution of (R)-1-(p-chlorobenzoyl)-3-aminopiperidine obtained in Example 14 (amount: 3 g). Themixture was stirred at 15° C. for 3 hours, and the precipitated crystalwas filtered off. The crystal was dried under reduced pressure to obtainthe title compound as white crystal (0.35 g, yield: 87%).

¹H NMR (400 MHz, CDCl₃): δ 7.43-7.28 (m, 4H), 4.57 (brs, 1H), 3.82-3.02(m, 4H), 1.98-1.22 (m, 13H)

Example 23 Method for producing(R)-1-(p-methylbenzoyl)-3-(benzyloxycarbonylamino)piperidine

Potassium carbonate (0.15 g) and benzyl chlorocarbonate (0.18 g) wereadded to the aqueous solution of(R)-1-(p-methylbenzoyl)-3-aminopiperidine obtained in Example 13(amount: 3 g). The mixture was stirred at 15° C. for 3 hours, andchlorobenzene (3 ml) and sodium chloride (0.5 g) were added. The mixturewas stirred at 90° C. for 10 minutes. The water layer was removed, andthe solvent was evaporated under reduced pressure to obtain the titlecompound as yellow oil (0.36 g, yield: 73%).

¹H NMR (400 MHz, CDCl₃): δ 7.46-7.20 (m, 9H), 5.22-4.82 (m, 3H),3.98-3.02 (m, 5H), 2.00-1.40 (m, 4H)

Example 24 Method for producing(R)-1-(p-chlorobenzoyl)-3-(benzyloxycarbonylamino)piperidine

Potassium carbonate (0.15 g) and benzyl chlorocarbonate (0.18 g) wereadded to the aqueous solution of(R)-1-(p-chlorobenzoyl)-3-aminopiperidine obtained in Example 14(amount: 3 g). The mixture was stirred at 15° C. for 3 hours, andchlorobenzene (3 ml) and sodium chloride (0.5 g) were added. The mixturewas stirred at 90° C. for 10 minutes. The water layer was removed, andthe solvent was evaporated under reduced pressure to obtain the titlecompound as yellow oil (0.16 g, yield: 35%).

¹H NMR (400 MHz, CDCl₃): δ 7.46-7.20 (m, 9H), 5.22-4.82 (m, 3H),3.98-3.02 (m, 5H), 2.00-1.40 (m, 4H)

Example 25 Method for producing (R)-1-benzoyl-3-aminopiperidine

Sodium hydroxide (7.4 g, 2 equivalents) and sodium hypochlorite (64.0 g,1.1 equivalents) were added to the aqueous solution of (R)-1-benzoylnipecotamide obtained in the method described in Example 10 (amount: 210g, net weight: 20.8 g). The mixture was stirred at 25° C. for 6 hours toobtain a solution (280.90 g) containing the title compound (17.7 g,yield: 97%).

¹H NMR (400 MHz, CDCl₃): δ 7.50-7.35 (m, 5H), 3.78-3.50 (m, 1H),3.04-2.64 (m, 4H), 2.06-1.24 (m, 4H)

Example 26 Method for producing (R)-1-benzoyl-3-(benzoylamino)piperidine

Concentrated hydrochloric acid is added to the solution obtained by themethod described in Example 25, and the pH of the mixture was adjustedto 9. Chlorobenzene (100 ml) is added to the mixture, and benzoylchloride (19.9 g, 1.5 equivalents) is added slowly thereto. The pH ofthe mixture was adjusted to from 7.0 to 9.0 using a 30% aqueous sodiumhydroxide solution. The mixture was stirred at 15° C. for 2 hours, andthe temperature was raised to 90° C., and then the mixture was stirredfor 30 minutes. The aqueous layer was separated, and the organic layerwas washed with an aqueous sodium bicarbonate solution (20 ml). Theorganic layer was concentrated under reduced pressure, and theprecipitated crystal was filtered off to obtain the title compound aswhite crystal (22.7 g, yield: 84%).

¹H NMR (400 MHz, CDCl₃): δ 8.19-7.26 (m, 10H), 6.18 (brs, 1H), 4.38-3.23(m, 5H), 2.32-1.48 (m, 4H)

Example 27 Method for producing (R)-3-aminopiperidine dihydrochloride

The crystal (21.2 g) obtained by the method described in Example 26 wasmixed with 6 N hydrochloric acid (160 ml), and the mixture was stirredat 100° C. for 14 hours. The internal temperature was cooled to 70° C.,and the mixture was washed with toluene (50 ml). The water layer wasconcentrated under reduced pressure, and isopropanol (50 ml) was addedto the concentrated mixture, and the mixture was further concentratedunder reduced pressure. The resulting white solid was dissolved inmethanol (60 ml), and then ethyl acetate (60 ml) was slowly addedthereto. The precipitated crystal was filtered off, and the titlecompound (10.8 g, yield: 92%, 99.5% ee) was obtained as white crystal.

¹H NMR (400 MHz, D₂O): δ 3.70 (d, 1H), 3.63 (tt, 1H), 3.46 (d, 1H),3.11-2.97 (m, 2H), 2.26 (brd, 1H), 2.12 (brd, 1H), 1.90-1.66 (m, 2H)

Example 28 Method for producing(R)-1-(tert-butoxycarbonyl)-3-aminopiperidine

To a solution (amount 9 g) of (R)-1-(tert-butoxy carbonyl)nipecotamide(net weigh of (R)-1-(tert-butoxycarbonyl) nipecotamide: 0.7 g), Sodiumhydroxide (1.3 g, 10 equivalents) and an aqueous sodium hypochloritesolution (2.2 g, 1.1 equivalents) were added. The mixture was stirred at15 to 25° C. for 16 hours. The water layer was removed, and the solventwas evaporated under reduced pressure. Toluene (10 ml) and saturatedbrine (5 ml) were added thereto, and the water layer was removed. Thesolvent was evaporated under reduced pressure to obtain the titlecompound as yellow oil (0.7 g, net weight: 0.5 g, yield: 80%).

Example 29 Method for producing (R)-3-aminopiperidine dihydrochloride

In isopropanol (3 ml), (R)-1-(tert-butoxycarbonyl)-3-amino piperidine(0.5 g) obtained by the method described in Example 28 was dissolved.The solution was slowly added dropwise into a 28% hydrogenchloride/isopropanol solution (5 ml), and the mixture was stirred for 3hours after completion of dropwise addition. The precipitated crystalwas filtered off to obtain the title compound as white crystal (0.4 g,yield: 98%).

Example 30 Method for producing (R)-1-benzoyl-(p-methylbenzoylamino)piperidine

To an aqueous solution of (R)-1-benzoylaminopiperidine (amount: 1.6 g,net weight of (R)-1-benzoylamino piperidine: 0.16 g) obtained by themethod described in Example 25, p-methylbenzoyl chloride (0.12 g, 1.5equivalents) was slowly added The pH of the mixture was adjusted to from7.0 to 9.0 using an 30% aqueous sodium hydroxide solution. The mixturewas stirred at 15° C. for 5 hours, and then the precipitated crystal wasfiltered off to obtain the title compound as white crystal (0.20 g,yield: 78%).

¹H NMR (400 MHz, CDCl₃): δ 7.80-7.05 (m, 9H), 6.06 (brs, 1H), 4.30-3.20(m, 5H), 2.40 (s, 3H), 2.32-1.46 (m, 4H)

Example 31 Method for producing (r)-1-benzoyl-3-(p-chlorobenzoylamino)piperidine

To an aqueous solution of (R)-1-benzoylaminopiperidine (amount: 1.6 g,net weight of (R)-1-benzoylamino piperidine: 0.16 g) obtained by themethod described in Example 25, p-chlorobenzoyl chloride (0.14 g, 1.5equivalents) was slowly added. The pH of the mixture was adjusted tofrom 7.0 to 9.0 using a 30% aqueous sodium hydroxide solution. Themixture was stirred at 15° C. for 5 hours, and then the precipitatedcrystal was filtered off to obtain the title compound as white crystal(0.25 g, yield: 92%).

¹H NMR (400 MHz, CDCl₃): δ 7.88-7.26 (m, 9H), 6.20 (brs, 1H), 4.30-3.22(m, 5H), 2.36-1.44 (m, 4H)

Example 32 Method for producing (R)-1-benzoyl-3-(benzoylamino)piperidine

Concentrated hydrochloric acid is added to the solution obtained by themethod described in Example 25 to adjust the pH to pH 9. Chlorobenzene(100 ml) is added thereto, and benzoyl chloride (19.9 g and 1.5equivalents) is added slowly thereto, and then the pH of the mixture wasadjusted to from 7.0 to 9.0 using a 30% aqueous sodium hydroxidesolution. The mixture was stirred at 15° C. for 6 hours, and then theprecipitated crystal was filtered off to obtain the title compound aswhite crystal (25.1 g, yield: 93%).

Example 33 Method for producing (R)-1-(benzyl)-3-amino piperidine

In (R)-1-(benzyl)nipecotamide (1.1 g) produced by the method describedin Example 2, water (5 ml), a 30% aqueous sodium hydroxide solution (6.7g, 10 equivalents), THF (10 ml), an aqueous sodium hypochlorite solution(11.2 g, 1.5 equivalents) were mixed. The mixture was stirred at 15° C.for 1 hour and at 60° C. for 2 hours. The mixture was cooled to 20° C.,and extracted with toluene (10 ml) three times. After the organic layerswere combined, the combined organic layer was concentrated under reducedpressure to obtain the title compound as yellowish brown oil (0.8 g,yield: 55%).

Example 34 Method for producing (R)-3-aminopiperidine dihydrochloride

To (R)-1-(benzyl)-3-aminopiperidine (pure amount: 18.9 g) produced bythe method described in Example 33, methanol (190 ml), concentratedhydrochloric acid (24.7 g, 2.5 equivalents) and 10 wt % Pd/C (1.9 g)were added sequentially. The air in the reactor vessel was substitutedby hydrogen. The mixture was stirred at 40° C. for 24 hours, and thecatalyst was filtrated. The filtrate was concentrated under reducedpressure to obtain the title compound as white crystal (21.5 g, yield:99%).

1-21. (canceled)
 22. A method for producing an optically active1-aroyl-3-(protected amino)piperidine derivative, comprising the stepsof: producing an optically active 1-aroyl-3-aminopiperidine derivativerepresented by the following formula (5):

wherein * indicates an asymmetric carbon atom and Ar represents anoptionally substituted aryl group having 6 to 15 carbon atoms, byHofmann rearrangement at the amide group of an optically active1-aroylnipecotamide derivative represented by the following formula (4):

wherein * and Ar mean the same as the above; and aroylating orcarbamating the amino group of formula (5) for crystallization orextraction to isolate the optically active 1-aroyl-3-(protectedamino)piperidine derivative represented by the following formula (6):

wherein * and Ar mean the same as the above; R² represents an optionallysubstituted aroyl group having 7 to 15 carbon atoms, an alkyloxycarbonylgroup having 2 to 15 carbon atoms, an alkenyloxycarbonyl group having 3to 15 carbon atoms, an aryloxycarbonyl group having 7 to 15 carbonatoms, or an aralkyloxycarbonyl group having 8 to 15 carbon atoms.
 23. Amethod for producing an optically active 3-aminopiperidine or saltthereof represented by the following formula (7):

wherein * indicates an asymmetric carbon atom, comprising a step ofhydrolyzing the compound (6) produced by the method according to claim22.